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- Pharmacokinetic data from the CHERISH study suggest that pregnant women treated with certolizumab pegol can maintain their dosing regimen throughout pregnancy
- An in vitro study found that rheumatoid factor (RF) antibodies bind to Fc-containing tumor necrosis factor inhibitors (TNFis) but are not able to bind to Fc-free certolizumab pegol – providing molecular insights towards more personalized therapeutic approaches in rheumatoid arthritis (RA)
- A separate post hoc analysis of the phase 3b REALISTIC trial suggests that in high RF patients with RA treated with certolizumab pegol, clinical responses to certolizumab pegol were similar over time, regardless of RF level including in TNFi inadequate responders
ATLANTA, June 13, 2024 – 07:00 (ET) – UCB, a global biopharmaceutical company, will present results from three studies for CIMZIA® (certolizumab pegol), a PEGylated fragment crystalized (Fc)-free tumor necrosis factor inhibitor (TNFi), for women of childbearing age living with chronic immune-mediated diseases and people with rheumatoid arthritis (RA) and high rheumatoid factor (RF) levels.1,2,3 These data will be presented at the European Congress of Rheumatology, EULAR 2024, and provide evidence to inform personalized treatment decisions for patient populations with high unmet need.
CHERISH study results (abstract POS0888)
Results from the open-label, phase 1b CHERISH study in women with immune-mediated diseases, including psoriatic arthritis (PsA), axial spondyloarthritis (axSpA), and RA, found that the range of blood plasma concentrations of certolizumab pegol throughout and after pregnancy were similar to those observed in studies of non-pregnant women with PsA, axSpA, and RA, suggesting that women may maintain stable therapeutic levels of certolizumab pegol throughout pregnancy.1
These data build on previous pharmacokinetic studies – CRIB and CRADLE – that showed minimal-to-no transfer from mother to baby through the placenta or breast milk.4,5 The latest study, CHERISH, expands on the data available by focusing on certolizumab pegol and stability of exposure for the mother.1 The safety profile observed in the CHERISH study was consistent with the known safety profile of certolizumab pegol, which includes extensive pharmacovigilance data.1 The CHERISH, CRIB, and CRADLE studies are pharmacokinetic studies. There are no adequate and well-controlled studies of CIMZIA in pregnant women or lactation to demonstrate efficacy or establish safety.
“Women of childbearing age living with chronic immune-mediated diseases are understandably concerned about how to ensure adequate disease control throughout pregnancy while preventing or minimizing exposure for their baby,” said Emmanuel Caeymaex, Executive Vice President, Head of Patient Impact, Chief Commercial Officer, UCB. “Through CHERISH and the full body of evidence we have built, we are equipping women and healthcare professionals with the data they need to make informed, personalized decisions around treatment continuation during family planning, pregnancy and breastfeeding. These studies underscore our commitment to serving specific subpopulations of patients with information that is directly relevant to them.”
RF-drug interaction research (abstract POS0722)
A further study presented at EULAR provided molecular insights into why individuals living with RA and high. RF levels generally maintain consistent drug concentrations and may experience consistent clinical outcomes when treated with certolizumab pegol.3,6 An in vitro study found that three different RF antibodies all bound to Fc-containing TNFi adalimumab and enabled the formation of large immune complexes. Conversely, the RFs were unable to interact with certolizumab pegol, due to its lack of Fc domain, and no complexes with RF were formed.3
REALISTIC trial results (abstract AB0638)
Insights into the effects of certolizumab pegol in people living with RA and high RF levels were investigated in a post-hoc analysis of the double-blind, placebo controlled, phase 3b REALISTIC trial – also accepted as an abstract at EULAR. Clinical response to certolizumab pegol was analyzed according to the highest quartile RF level compared with the lowest and in people with a previous inadequate response to TNFi versus those with no prior TNFi exposure.2 Responses were greater with certolizumab pegol versus placebo in all groups. In patients who previously had an inadequate response to TNFis, responses among those who were randomized to placebo were lower in the high RF group compared with the low RF group at week 12. By contrast, clinical responses to certolizumab pegol treatment were similar between those with high and with low RF levels, indicating that RF level does not influence a patient’s response to certolizumab pegol.2
“For people living with RA, high RF levels are associated with more severe disease activity, risk of progression and loss of treatment efficacy, so the encouraging results of the REALISTIC study may impact treatment choices for people living with RA and high RF levels who have previously had an inadequate response to TNFis,” said Dr James Galloway, investigator on the REALISTIC trial, Professor of Rheumatology at King’s College London and an honorary Consultant in Rheumatology at King’s College Hospital, London. “The RF-drug interaction research also presented at EULAR provides important molecular insights in to why we see more consistent drug concentrations among high RF patients treated with certolizumab pegol compared with Fc-containing TNFis.”
These certolizumab pegol data together demonstrate how tailored treatment approaches can support specific groups of patients.
Dr. Oseme Etomi, Consultant Rheumatologist and Obstetric Physician, Guy’s and St Thomas Hospitals, London, said, “Chronic rheumatological diseases such as axSpA, RA, and PsA are multifactorial and present significant treatment challenges, particularly as patients progress through different stages of life, such as family planning, pregnancy and breastfeeding, or disease progression. The new clinical data we’ve seen at EULAR are valuable to support more personalized treatment that is tailored to the individual needs, lifestyle choices and clinical profile of each patient.”
For further information, contact UCB:
Investor Relations
Antje Witte
T: +32.2.559.94.14
email antje.witte@ucb.com
U.S. Communications
Nicole Herga
T: +1.773.960.5349
email nicole.herga@ucb.com
Notes to editors:
About CHERISH1
The CHERISH study was a multicenter, longitudinal, interventional, prospective, open-label phase 1B exploratory study evaluating the impact of pregnancy on the pharmacokinetics of certolizumab pegol. The study consisted of a screening period, pregnancy period (up to 40 weeks), post-partum period (up to 13 weeks), and a safety follow-up contact (five weeks after final study visit). CHERISH investigated the blood concentrations of certolizumab pegol during and after pregnancy, alongside monitoring any adverse events.
Twenty-one women, nine of them with rheumatoid arthritis, were enrolled into CHERISH when up to 10 weeks pregnant and having been on a stable maintenance dose of certolizumab pegol (either 200 mg or 400 mg every two weeks, or 400 mg every four weeks) for at least 12 weeks.
Blood samples were taken pre-dose every four weeks during pregnancy and once at roughly 12 weeks post-partum, as well as one week after a certolizumab pegol dose every eight weeks during pregnancy and once post-partum. The participants were contacted for a safety follow-up after another five weeks.
All observed concentrations of certolizumab pegol were within the range seen in non-pregnant patients with psoriatic arthritis, axial spondyloarthritis, and rheumatoid arthritis (1.7-45.3 µg/ml). Levels of certolizumab pegol remain consistent throughout pregnancy, although they were somewhat lower during pregnancy than post-partum. The adverse event profile was consistent with the known profile of certolizumab pegol, and no safety concerns were reported.
The findings from CHERISH suggest that women may continue certolizumab pegol at their usual dose and expect to maintain stable therapeutic levels throughout pregnancy.
About CRIB and CRADLE
CRIB was a pharmacokinetic study of women ≥30 weeks pregnant receiving commercial certolizumab pegol for a locally approved indication (last dose ≤35 days prior to delivery).
Blood samples were taken from mother, infant, and umbilical cord at birth, and again from the baby at four and eight weeks of age, to assess whether certolizumab pegol is transferred to infants via the placenta.
Of the 16 women who participated, eleven were receiving certolizumab pegol for rheumatoid arthritis, three for Crohn’s disease, one for psoriatic arthritis, and one for axial spondyloarthritis/ankylosing spondylitis; all had healthy pregnancies, and 14 of the babies gave samples that could be included in the study.
Using a specific, sensitive assay, levels of certolizumab pegol in the mothers at delivery were found to be in the therapeutic range, whereas the level was below measurable in 13 of the newborns. In the fourteenth infant, a minimal level of certolizumab pegol was detected, equivalent to 0.09% of the maternal level and considered unlikely to have any effect. By weeks four and eight, certolizumab pegol was undetectable in all the babies.
There were no patterns of adverse events in the babies to suggest any difference from children of mothers not treated with certolizumab pegol, while safety data in the mothers were consistent with the known profile of certolizumab pegol and of the underlying diseases in pregnancy.
Thus, CRIB showed minimal to no placental transfer of certolizumab pegol from mother to infant, supporting continuation of treatment throughout pregnancy when clinically needed.
CRADLE was a pharmacokinetic study of lactating mothers receiving certolizumab pegol.
The study assessed whether certolizumab pegol is transferred into breast milk and the level of dose an infant might be exposed to.
The 17 women involved were receiving certolizumab pegol (seven for rheumatoid arthritis, five for Crohn’s disease, three for psoriatic arthritis, and two for axial spondyloarthritis/ankylosing spondylitis) and had chosen to breastfeed – both decisions were made independent of the study.
Mothers provided milk samples during at-home visits starting at least six weeks post-partum, to allow breastfeeding routine to be established undisturbed, beginning with a pre-dose sample on the day of their certolizumab pegol dose, and then every two days for two weeks. One mother on a four-week dose schedule gave one additional pre-dose sample at four weeks.
Certolizumab pegol levels were below measurable in 77 of 137 milk samples tested (56%), while the remainder had minimal levels, all less than 1% of the expected level in the blood of an adult receiving a therapeutic maintenance dose. A relative infant dose (RID) below 10% is considered unlikely to be of concern to infant wellbeing. The mean RID for certolizumab pegol was calculated to be below 0.5% of the maternal dose and the median RID was 0.15%.
Adverse events in the infants of mothers treated with certolizumab pegol were consistent with those occurring in unexposed infants of similar age, while those in the mothers were consistent with the known safety profile of certolizumab pegol.
With results indicating minimal to no transfer into breast milk, CRADLE showed that continued treatment with certolizumab pegol is compatible with breastfeeding.
About REALISTIC2
REALISTIC (RA Evaluation in Subjects Receiving TNF Inhibitor Certolizumab Pegol) was a multicenter phase 3b trial in patients with active rheumatoid arthritis who had shown inadequate response to disease-modifying antirheumatic drugs, including patients with/without prior TNFi exposure, with/without concomitant methotrexate or other disease-modifying anti-rheumatic drugs (DMARDs);), and varying lengths of disease duration. The study demonstrated that – in a diverse group of RA patients reflecting those seen in daily clinical practice (including those with prior TNF-inhibitor use) – addition of certolizumab pegol to current therapy was associated with a rapid and consistent clinical response, including improved physical function and reduced disease activity.
Patients with active RA with inadequate response to ≥1 DMARD were randomized 4:1 to subcutaneous injections of certolizumab pegol 400 mg at Weeks 0, 2, and 4 followed by 200 mg every 2 weeks or placebo injection (control) every 2 weeks + current therapy. Primary outcome was ACR20 at Week 12. Randomization was stratified by prior TNF inhibitor use, concomitant use of methotrexate (MTX), and disease duration (<2 y vs ≥2 y).
About CIMZIA® in the U.S.7
CIMZIA® is the only Fc-free, PEGylated anti-TNF (tumor necrosis factor). CIMZIA has a high affinity for human TNF-alpha, selectively neutralizing the pathophysiological effects of TNF-alpha.
CIMZIA is also indicated for the treatment of adults with moderately to severely active rheumatoid arthritis (RA), adults with active psoriatic arthritis (PsA), adults with active ankylosing spondylitis (AS), and adults with active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation.
CIMZIA is indicated for the treatment of moderate-to-severe plaque psoriasis (PSO) in adults who are candidates for systemic therapy or phototherapy.
In addition, CIMZIA is indicated for reducing signs and symptoms of Crohn's disease (CD) and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.
See important safety information including risk of serious bacterial, viral and fungal infections and tuberculosis below.
IMPORTANT SAFETY INFORMATION about CIMZIA in the U.S.
CONTRAINDICATIONS
CIMZIA is contraindicated in patients with a history of hypersensitivity reaction to certolizumab pegol or to any of the excipients. Reactions have included angioedema, anaphylaxis, serum sickness, and urticaria.
SERIOUS INFECTIONS
Patients treated with CIMZIA are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.
Discontinue CIMZIA if a patient develops a serious infection or sepsis.
Reported infections include:
- Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before CIMZIA use and during therapy. Initiate treatment for latent TB prior to CIMZIA use.
- Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.
- Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.
Carefully consider the risks and benefits of treatment with CIMZIA prior to initiating therapy in the following patients: with chronic or recurrent infection; who have been exposed to TB; with a history of opportunistic infection; who resided in or traveled in regions where mycoses are endemic; with underlying conditions that may predispose them to infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with CIMZIA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.
- Do not start CIMZIA during an active infection, including localized infections.
- Patients older than 65 years, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants may be at greater risk of infection.
- If an infection develops, monitor carefully and initiate appropriate therapy.
MALIGNANCY
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which CIMZIA is a member. CIMZIA is not indicated for use in pediatric patients.
- Consider the risks and benefits of CIMZIA treatment prior to initiating or continuing therapy in a patient with known malignancy.
- In clinical trials, more cases of malignancies were observed among CIMZIA-treated patients compared to control patients.
- In CIMZIA clinical trials, there was an approximately 2-fold higher rate of lymphoma than expected in the general U.S. population. Patients with rheumatoid arthritis, particularly those with highly active disease, are at a higher risk of lymphoma than the general population.
- Malignancies, some fatal, have been reported among children, adolescents, and young adults being treated with TNF blockers. Approximately half of the cases were lymphoma, while the rest were other types of malignancies, including rare types associated with immunosuppression and malignancies not usually seen in this patient population.
- Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including CIMZIA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn's disease or ulcerative colitis, and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. Carefully assess the risks and benefits of treating with CIMZIA in these patient types.
- Cases of acute and chronic leukemia were reported with TNF blocker use.
HEART FAILURE
- Worsening and new onset congestive heart failure (CHF) has been reported with TNF blockers. Exercise caution and monitor carefully.
HYPERSENSITIVITY
- Angioedema, anaphylaxis, dyspnea, hypotension, rash, serum sickness, and urticaria have been reported following CIMZIA administration. If a serious allergic reaction occurs, stop CIMZIA and institute appropriate therapy. The needle shield inside the removable cap of the CIMZIA prefilled syringe contains a plastic derivative of natural rubber latex which may cause an allergic reaction in individuals sensitive to latex.
HEPATITIS B VIRUS REACTIVATION
- Use of TNF blockers, including CIMZIA, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases have been fatal.
- Test patients for HBV infection before initiating treatment with CIMZIA.
- Exercise caution in patients who are carriers of HBV and monitor them before and during CIMZIA treatment.
- Discontinue CIMZIA and begin antiviral therapy in patients who develop HBV reactivation. Exercise caution when resuming CIMZIA after HBV treatment.
Abbreviations: HBV: hepatitis B, RA: rheumatoid arthritis, RF: rheumatoid factor, TNF: tumor necrosis factor.
NEUROLOGIC REACTIONS
- TNF blockers, including CIMZIA, have been associated with rare cases of new onset or exacerbation of central nervous system and peripheral demyelinating diseases, including multiple sclerosis, seizure disorder, optic neuritis, peripheral neuropathy, and Guillain-Barré syndrome.
HEMATOLOGIC REACTIONS
- Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Medically significant cytopenia has been infrequently reported with CIMZIA.
- Consider stopping CIMZIA if significant hematologic abnormalities occur.
DRUG INTERACTIONS
- Do not use CIMZIA in combination with other biological DMARDS.
AUTOIMMUNITY
- Treatment with CIMZIA may result in the formation of autoantibodies and, rarely, in development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.
IMMUNIZATIONS
- Patients on CIMZIA should not receive live or live-attenuated vaccines.
ADVERSE REACTIONS
- The most common adverse reactions in CIMZIA clinical trials (≥8%) were: upper respiratory infections (18%), rash (9%), and urinary tract infections (8%).
For full prescribing information, please visit https://www.ucb-usa.com/cimzia-prescribing-information.pdf.
Abbreviations: ACR: American College of Rheumatology, AS: ankylosing spondylitis; axSpA: axial spondyloarthritis, CD28: cluster of differentiation 28 (a protein expressed on T cells), CRP: C-reactive protein, DMARDs: disease-modifying antirheumatic drugs, EEA: European Economic Area, EU: European Union, HBV: hepatitis B virus, MRI: magnetic resonance imaging, MTX: methotrexate, NSAIDs: non-steroidal anti-inflammatory drugs, RA: rheumatoid arthritis, RF: rheumatoid factor, TNFis: tumor necrosis factor inhibitors.
About UCB
UCB, Brussels, Belgium (www.ucb.com) is a global biopharmaceutical company focused on the discovery and development of innovative medicines and solutions to transform the lives of people living with severe diseases of the immune system or of the central nervous system. With approximately 9,000 people in approximately 40 countries, the company generated revenue of €5.3 billion in 2023. UCB is listed on Euronext Brussels (symbol: UCB). Follow us on Twitter: @UCB_USA.
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References
- Clowse ME, et al. Pharmacokinetics of certolizumab pegol in pregnancy: results from the open-label, phase 1b CHERISH study. EULAR, Vienna, 12-15 June 2024. Abstract POS0888.
- Smolen JS, et al. Do high rheumatoid factor levels impact response to certolizumab pegol in patients with inadequately controlled rheumatoid arthritis? A post hoc analysis of the phase 3b REALISTIC trial. EULAR, Vienna, 12-15 June 2024. Abstract number AB0638.
- Bidgood SR, et al. Purified monoclonal rheumatoid factors bind Fc containing TNF inhibitors in vitro but not the Fc-free TNF inhibitor, certolizumab pegol. EULAR, Vienna, 12-15 June 2024. Abstract POS0722.
- Mariette X, et al. Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study. Ann Rheum Dis. 2018;77(2):228-33.
- Clowse ME, et al. Minimal to no transfer of certolizumab pegol into breast milk: results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study. Ann Rheum Dis. 2017;76(11):1890-6.
- Smolen J, et al. Do High RF Titers Impact Response to TNF Inhibitors? Comparison of Certolizumab Pegol and Adalimumab in Patients with RA and High Titers of RF: A Post Hoc Analysis of a Phase 4 Trial. Rheumatology. 2024;63(suppl 1):75-76.
- CIMZIA (certolizumab pegol) [prescribing information]. Smyrna, GA: UCB, Inc.
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